Derivatives indolene in the form of a racemate or an optically active isomer or pharmaceutically acceptable salt additive acid and ketoprofen indolene

 

(57) Abstract:

Usage: in the chemistry of indolones, in particular derivatives indolene in the form of a racemate or an optically active isomer or pharmaceutically acceptable salt and ketoprofene indolene. The inventive product connection f-crystals I and II, where X - link f-l III - V with the corresponding values radicals. Reagent 1: ketoprofene f-ly II. Reagent 2: sodium borohydride. Reaction conditions: alcohol medium at 15 - 45oC. the structure of the compounds f-crystals I and II

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where

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2 C. and 8 C.p. f-crystals, 1 table.

The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates.

Ifenprodil is racemic, so nazwa as antihypertensives, the usefulness distributed on the row closest analogues. Ifenprodil, as shown, also has anti-ischemic activity and activity block induced by amino acid receptor.

The purpose of the invention, the detection of compounds with neuroprotective action in an appropriate degree, at the same time having low or negligible hypotensive effect.

Some structurally related 1-phenyl-3-(4-aryl-4-acrocephalidae)-1-propanol are useful as analgesics, 1-[4-(amino - and hydroxy-alkyl)-phenyl]-2-(4-hydroxy-4-callipering)-1-alkanols and alkenone, are analgesic, hypotensive, psychotropic or anti-inflammatory activity.

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in which Raand Rbeach independently is hydrogen or (C1-C4)alkyl,

Rcis benzyl, phenoxy-, benzyloxy group or phenoxymethyl, and

Zais CH2C(CH3)2or CH2CH2have neuroprotective activity type.

The invention relates to racemic or optically active compounds of the formula:

,

where

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< / BR>
in which

And is a group of the formula:
2each independently is hydrogen or (C1-C3)-alkyl;

R3and R4taken separately, each is hydrogen, or

R3and R4taken together are ethylene;

X is hydrogen, (C1-C3)-alkoxy group, or (C1-C3)-alkoxy-carbonyl;

Y is CH2or oxygen;

Z and Z1each independently is hydrogen, (C1-C3)-alkyl, (C1-C3)-alkoxy group, fluorine, chlorine or bromine; and their pharmaceutically acceptable salts accession acids.

Preferred compounds of the invention in most cases, we have R2in the form of hydrogen or methyl, most preferably in the form of bromide, having the relative stereochemistry of 1-oxypropylene side chain, depicted as formula

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and who is either (1S*, 2S*), or as (1R*THAT 2R*).

The preferred values are in most cases

(forming 2(1H,3H)-indole or oxindol);

(forming a 3,4-dihydro-2(1H)-hinolan);

(forming indole);

and

(forming 2(3H)-benzoxazolone).

The invention relates also to an intermediate connection is.

The invention relates also to pharmaceutical compositions comprising a compound of formula (I), (II) or (III), and to a method of treatment of stroke, traumatic brain injury or degenerative diseases of the CNS using the compounds of formula (I), (II) or (III).

The expression "pharmaceutically acceptable salt accession acid" is intended to include, but not for the limitations of such salts as the hydrochloride, bromohydrin, loggedout, nitrate, hydrosulfate, dihydrophosphate, mesilate, maleate and succinate. Such salts are obtained by reaction of the free basic form of compound (I), (II) or (III) with an appropriate acid, usually one molar equivalent, and solvent. Those salts which do not precipitate directly, in most cases highlighted by concentrating the solvent and/or by adding a non-solvent (a substance that does not cause dissolution).

The compounds of formula (I) to (VI), which in the Central part of the molecule is 1-alkanols have asymmetric C-1 carbon atom, whereas those compounds in which R is not hydrogen, have a second asymmetric center at C-2 carbon atom of alkanol. Similarly, the compounds of formulas (IV) (VI), which are 1 can be split into optical isomers, showing equal but opposite rotation of plane-polarized light. For example, all these compounds potentially split by fractionated crystallization of their diastereomeric salts with accession optically active acid, as it provides an example below in the description. Alcohols also potentially split using chromatography or fractional crystallization esters or urethanes obtained by the reaction with activated forms of optically active acids or optically active isocyanates, as it also provides an example below in the description. Thus, the invention should not be construed as limited racemic forms of the compounds of the invention.

Compounds of the invention having the formula (I), (II) and (III) are obtained easily.

Ketones-predecessors in most cases obtained by nucleophilic substitution of suitably substituted 2-halogen, 2-alkanesulfonyl - or 2-arylsulfonate-1-Alcanena using the appropriate substituted piperidine derivative, for example

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in which X is typically chlorine, bromine, mesilate or tosyloxy group. This reaction is carried out under conditions typical can be used essentially amounts, close to the molar equivalents; though, when one of the reagents is more readily available, is generally preferred to use this reagent in excess, in order to expedite the completion of this bimolecular reaction in a shorter period of time. The reaction in most cases is carried out in the presence of at least 1 molar equivalent of base, the derivative of piperidine, if it is readily available, but is more typically a tertiary amine, which is at least comparable in the main power with the nucleophilic piperidine; and in a solvent inert to the reaction, such as ethanol. If necessary, the reaction is catalyzed by the addition of up to one molar equivalent or more iodide salts (e.g., NaI, KI). Temperature is not the decisive factor, but in most cases it will be relatively increased in order to accelerate the completion of the reaction within a shorter period of time, but not so high as to cause excessive decomposition. The temperature in the range of 50 120oSince in most cases is satisfactory. Preferably, when the temperature is the boiling temperature of the reaction mixture with reverse drains phlegmy.

The use of the em source substances, reagents, intermediates or reaction products to a certain degree, which adversely affects the yield of the desired reaction product.

The resulting intermediate ketones conveniently converted to corresponding alcohols by conventional recovery using NaBH4usually in excess, in proton solvent such as methanol or ethanol, in most cases at a temperature in the range of about 15 45oC.

Source materials and reagents required for the synthesis of compounds of the invention are readily available, either commercially, according to literature methods, or by methods that are provided by the example below in the section Received (the Drug).

Compounds of the invention of formula (I), (II) and (III) have a selective neuroprotective activity, based on their anti-ischemic activity and the ability to block induced by amino acid receptors, at the same time, for the most part has a reduced or negligible hypotensive activity. Anti-ischemic activity of the compounds of the invention is defined by one or more methods, which are discussed in detail previously Gotti and others and Carter and others, cited above, or pottery evidenced by their ability to block induced by N-methyl-D-aspartic acid (N) increase (elevation) CG Mr in the cerebellum of newborn rat according to the following procedure. The cerebellum from ten rats of Wistar 8 to 14 days of age quickly cut out and placed at 4oC in Krebs/bicarbonate buffer, pH 7.4, and then cut into pieces with a size of 0.5 x 0.5 mm, using a fabric knife Macilwaine (nickl, Laboratory Engineering Bldg. Gomshall, Sari, England). The resulting pieces of the cerebellum are transferred to 100 ml of Krebs/bicarbonate buffer at 37oWith that continuously equilibrated with 95: 5 mixture of O2/CO2. Slices of the cerebellum are incubated in this way for 90 min with three changes of buffer. Then the buffer is decanted, the fabric is centrifuged (1 min, 3200 rpm) and tissue re-suspendered in 20 ml of Krebs/bicarbonate buffer. Then remove 250 ál aliquot samples (approximately 2 mg) and placed in a small (microfuge) tubes of 1.5 ml In these tubes are added 10 μl of the compounds from the primary solution followed, after a 10-minute incubation period, add 10 μl of a 2.5 mm solution NMDK to start the reaction. The final concentration NMDK is 10 μm. Control samples are not added NMDK. The tubes are incubated for 1 min at 37oWith a shake in a water bath, and then added 750 μl of 50 mm Tris-C1, 5 mm solution etc (this is bath for 5 minutes The contents of each tube is destroyed then the ultrasound for 15 s, using a setting of ultrasonic treatment on the sample at power level three. Retrieved 10 μl of the sample, and the protein is determined by the method of Lowry, Ana I. Biochem. 100: 201 220 (1979). The tubes then centrifugeuse (5 min, 10.000 XA), extracted with 100 µl of the supernatant liquid, and the level of cyclic G Mrs (CG Mr) is analyzed by using radioimmunoassay CG Mr from new England Nuclear (Boston, mA) according to the manufacturer. Data are reported as pmol CG Mr generated per mg of protein. Unwanted hypotensive activity is also determined by known methods, for example, methods Cerrone and others also cited above.

Such selective neuroprotective anti-ischemic activity and activity block induced by amino acid receptors reflect the valuable utility of the compounds of the invention in the treatment of stroke, traumatic brain injury and degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Parkinson's disease and Huntington's disease, without significant capacity on parallel excessive fall croviana the uly (I), (II) or (III), the dosage is typically around 0.02 to 10 mg/kg/day (1,500 mg/day for the average person weighing 50 kg) in one (single) or separated (small) doses, regardless of the route of administration. Depending on the desired connection and the specific nature of a particular disease, the dose beyond this limit may be prescribed by the attending physician. The oral route of intake is preferred in most cases. However, if the patient is unable to swallow, or oral absorption in other cases, harm, then the preferred route of administration is parenteral (intramuscular, intravenous) or outdoor fashion destination.

Compounds of the invention in most cases are assigned in the form of pharmaceutical compositions comprising at least one of the compounds of formula (I), (II) or (III), together with a pharmaceutically acceptable excipient or diluent. Such compositions, in most cases, are prepared in the usual way, using solid or liquid fillers or diluents, which correspond to the way a specific purpose: for oral administration in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders, etc. for parenteral destination in the form injen ointments and the like.

Example 1.

5-[2-(4-Benzyl-4-oxopiperidine)-propionyl]-2(1H,3H)-indole

5-(2-Chloropropionyl)-2-(1H, 3H)-indole (2.5 g, and 11.2 mmol), 4-hydroxy-4-benzylpiperidine (2.1 g, and 11.2 mmol) and triethylamine (1,56 ml, and 11.2 mmol) are mixed in ethanol and refluxed overnight. The mixture is cooled to room temperature and concentrate under reduced pressure. The remainder is divided into parts between ethyl acetate and water and the phases are separated. The aqueous layer was extracted with ethyl acetate and the combined organic phase was washed with brine, dried over calcium sulfate and concentrated. The crude reaction product is subjected to flash chromatography on silica gel, elwira first unreacted 5-(2-chloropropionyl)-2-(1H,3H)-indole using a 1: 1 mixture of ethyl acetate: hexane. Further elution with ethyl acetate to give 3.6 g of the reaction product in the form of a light brown foamy substance. Recrystallization from ethyl acetate/hexane gives 1,23 g purified the above-mentioned reaction product. Less pure fractions from the column and the mother liquor from the recrystallization re chromatographic as described above using a 1: 1 mixture, and then 3:1 mixture of ethyl acetate:hexane. The fraction of the reaction product is ground to powder coated examination bed with the 88 192oC.

NMR by 8.22 (singlet, 1H), 8,08 (doublet, J 8 Hz, 2H), 7,99 (singlet, 1H), 7,31 7,13 (multiplet, 5H), 6.89 in (doublet, J 8 Hz, 1H), 4,03 (Quartet, J 6.8 Hz, 1H), 3,57 (singlet, 2H), 2,72 (singlet, 2H), 2,72 2,58 (multiplet, 3H), 2,46 (distorted triplet, 1H), 1,75 1,40 (multiplet, 4H), 1.26 in (doublet, J 6.8 Hz, 3H), 1,23 1,19 (multiplet, 1H).

Calculated for C23H26N2O3C 72,99; N 6,92; N 7,40.

Found, With 72,68; N 6,77; N 7,28.

Example 2.

5-[2S*-(4-Benzyl-4-oxopiperidine)-1S*-oksipropil] -2(1H,3H)-indole

The reaction product from example 1 (0.75 g, to 1.98 mmol) is dissolved in 50 ml of hot ethanol and allowed to cool. The solution is added dropwise within 1 to 2 min to a slurry of borohydrate sodium (0,113 g, 2,98 mmol) in ethanol (50 ml) together with 25 ml of ethanol for washing. The mixture is stirred over night. Add water (2 ml) and the solvent is removed under reduced pressure. The remainder is divided into parts between layers of ethyl acetate and water. Note that a small number of dithionite add to all water leaching to prevent air oxidation of the reaction products. The organic layer was separated, washed with saline, dried over calcium sulfate and concentrated to yield a white solid. This substance-her on silica gel with elution by ethyl acetate, to get to 0.19 g of additional quantity of the reaction product with a total yield of 0.43 g, 57 so pl. 228 229oC.

NMR 7,66 (broadened singlet, 1H), 7,31 7,10 (multiplet, 7H), 6,77 (doublet, J 8 Hz, 1H), 4,17 (doublet, J 10 Hz, 1H), 3,49 (singlet, 2H), 2,84 (doublet and triplet, J 2.5 and 11 Hz, 1H), was 2.76 (singlet, 2H), 2,40 2,65 (multiplet, 4H), 1,86 1,50 (multiplet, 5H), 1,15 (singlet, 1H), 0,76 (doublet, J 6.5 Hz, 3H).

Analysis calculated for C23H28N2O3WITH 72,61; N 7,42; N OF 7.36.

Found, With 73,04; N 7,50; N 7,35.

Example 3.

5-[2S*-(4-Hydroxy-4-phenylpiperidine)-1S*-oksipropil] -2(1H,3H)-indole

According to the methods of examples 1 and 2 4-hydroxy-4-phenylpiperidine turn to appear in the title of the reaction product with 38% overall yield. The reaction product is purified on a flash chromatography on silica gel and ground to powder using ethyl acetate; so pl. 216 218oC.

NMR 7,51 (doublet, J 9 Hz, 3H has the NH proton in this singlet), was 7.36 (triplet, J 7.5 Hz, 2H), 7,24 (doublet and triplet, J 1.2 and 7.5 Hz, 2H), 7,17 (two doublet, J 1.2 and 7.5 Hz, 1H), 6,78 (doublet, J 8 Hz, 1H), 4,22 (doublet, J 10 Hz, 1H), 3,51 (singlet, 2H), is 3.08 (doublet and triplet, J 2 and 11 Hz, 1H), 2,7 2,48 (multiplet, 5H), 2,24 1,98 (multiplet, 2H), 1,83 - 1,70 (broadened doublet, 2H), 1,49 (singlet, 1H), 0,82 (doublet, J 7 Hz, 3H).

Analysis, P> Example 4.

5-[2S*-(4-Hydroxy-4-phenylpiperidine)-1S*-oksipropil] -3-methyl-2(1H,3H)-indole

According to the method of examples 1 and 2 make 5-(2-chloropropionyl)-3-methyl-2(1H, 3H)-indole and 4-hydroxy-4-phenylpiperidine up above in the title of the reaction product from 24 th input: so pl. 219 220oC (from ethyl acetate).

Example 5.

5-[2-(4-Hydroxy-4-phenylpiperidine)-propionyl] -1-(para-toluene-sulfonyl)-indole

5-(2-Bromopropionyl)-1-(para-toluensulfonyl)-indole (1,67 g, 3,37 mmol, 83-Noah purity) dissolved in hot ethanol (100 ml) and add 4-hydroxy-4-phenylpiperidine (0.6 g, 3,39 mmol) and triethylamine (0,94 ml, 6,74 mmol). The mixture is refluxed over night. The reaction mixture is cooled and concentrated directly onto silica gel and subjected to flash chromatography. Elution with 1:3 mixture of ethyl acetate:hexane removes 0.1 g not subjected to bromirovanii ketone. Sequential elution with 1:1 mixture of ethyl acetate: hexane gives 1.47 g 87 the above-mentioned reaction product as a glassy orange solid.

NMR to 8.34 (singlet, 1H), 8,09 (doublet, J 9 Hz, 1H), 8,00 (doublet, J 8.5 Hz, 1H), to 7.77 (doublet, J 8.5 Hz, 2H), to 7.61 (doublet, J 3.5 Hz, 1H), 7,45 (doublet, J 9 Hz, 2H), 7,33 7,29 (multiplet, 2H), 7.24 to 7,21 (multiplet, 4H is tiplet, 1H), 2.05 is 1,97 (multiplet, 1H), 1,66 1,77 (multiplet, 1H), 1,59 1,54 (multiplet, 1H), 1,31 (doublet, J 7 Hz, 3H).

IR 1679, 1605, 1375, 1289, 1260, 1169, 1126, 994.

FAB HRMS calculated for C29H31N2O4S (MH+): 503, 2006.

The observed m/e: 503, 2023.

Example 6.

5-[2-(4-Hydroxy-4-phenylpiperidine)-propionyl]-indole

The reaction product from the previous example (1.3 g, a 2.75 mmol) dissolved in methanol (50 ml) and the whole of potassium hydroxide (0,324 g, 5,79 mmol) is added in one step. The mixture is boiled with reverse drains phlegmy for 6 h, then cooled and the solvent is removed under reduced pressure. The remainder is divided into parts between layers of ethyl acetate and water. The phases are separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over calcium sulfate and concentrated. The residue is subjected to flash chromatography on silica gel using 1:1 mixture of ethyl acetate: hexane by elution to obtain 0,719 g, 75 the above reaction product in the form of a glassy solid: so pl. 60 70oC.

NMR charged 8.52 (singlet, 1H), 8,49 (broadened singlet, 1H), 8,00 (two doublet, J 1.5 and 8.5 Hz, 1H), 7,49 7,41 (multiplet, 3H), 7,35 7,21 (multiplet, 4H), 6,67 (singlet, 1H), 4,30 is oblet, J 6.5 Hz, 3H).

IR (l3): 3470, 2924, 1673, 1613, 1412, 1348, 1323, 1276, 1224, 1115.

FAB HRMS calculated for C22H25N2O4(MH+): 349, 1918.

The observed m/e: 349, 1930.

Example 7.

5-[2S*(4-Hydroxy-4-phenylpiperidine)-1S*-oksipropil]-indole

The reaction product from the previous example restores according to the method of example 2. Presents the above-mentioned reaction product is obtained as a fluffy white solid with a 15% yield after chromatography on silica gel and recrystallization from ethanol: so pl. 220,5 221oC.

NMR 8,15 (broadened singlet, 1H), 7,63 (singlet, 1H), 7,54 (doublet, J 8.5 Hz, 2H), 7,38 (triplet, J 7.5 Hz, 3H), 7,30 7,19 (multiplet, 3H), 6,53 (singlet, 1H), 4,39 (doublet, J 10 Hz, 1H), is 3.08 (doublet and triplet, J 2 and 11.5 Hz, 1H), 2,90 2,62 (multiplet, 4H), 2,10 2,35 (multiplet, 2H), 1,90 1,80 (multiplet, 2H), 0,82 (doublet, J 6.5 Hz, 3H).

IR (l3): 3475, 2922, 1731, 1376, 1250, 1201, 1038.

Analysis calculated for C22H26N2O2WITH 75,40; N. OF 7.48; N 7,99.

Found, With 74,99; N 7,47; N To $ 7.91.

Example 8.

5-[2-(4-Benzyl-4-oxopiperidine)-acetyl]-2(1H,3H)-indole

A mixture of 5-(chloroacetyl)-2(1H,3H)-indolene (2,05 g, 9,78 mmol), 4-hydroxy-4-benzylpiperidine (1,87 g, 9,78 mmol), Carbo is phlegmy during the night. The reaction mixture was cooled and filtered through a layer of celite. The filtrate is concentrated to obtain an orange foamy substance which is subjected to flash chromatography on silica gel by elution with ethyl acetate. This leads to 0,79 g of an oily yellow solid reaction product.

NMR 9,41 (broadened singlet, 1H), to $ 7.91 (doublet, J 8 Hz, 1H), 7,86 (singlet, 1H), 7,28 7,14 (multiplet, 5H), 6.90 to (doublet, J 8 Hz, 1H), 3,76 (singlet, 2H), 2,52 (singlet, 2H), 2,78 2,73 (multiplet, 4H), 2,43 (triplet, J 10.5 Hz, 2H), 1,86 1,76 (multiplet, 2H), 1,50 (broadened doublet, J 12 Hz, 2H), 1,36 (broadened singlet, 1H).

IR (KBr): 2920; 2815, 1710, 1685, 1615, 1240, 1115.

FAB HRMS calculated for C22H25N2O3(MH+): 365, 1867.

The observed m/e): 365, 1883.

Example 9.

5-[2-(4-Benzyl-4-oxopiperidine)-1-oxyethyl]-2(1H,3H)-indole

The restoration is carried out with the reaction product from the previous example by the method of example 2. The product was then purified using flash chromatography and recrystallization from ethyl acetate, to obtain presents in the name of the reaction product in the form of a reddish-brown solid with 18-s ' output: so pl. 168,5 169, 5mmoC.

NMR 8,40 (broadened singlet, 1H), 7,35 7,17 (multiplet, 7H), 6,80 (doublet, J is ipled, 6N), 1,83 1,67 (multiplet, 2H), 1,59 1,52 (multiplet, 2H), 1.27mm (broadened singlet, 1H).

IR (KBR): 3420, 3170, 2945, 1820, 1705, 1625, 1490, 1320, 1115, 830, 707.

FAB HRMS calculated for C22H27N2O3(MH+): 367,2023.

The observed m/e): 367, 2061.

Example 10.

5-[2-(4-Hydroxy-4-phenylpiperidine)-1-oxyethyl]-2(1H,3H)-indole

According to the methods of examples 8 and 2, 4-hydroxy-4-phenylpiperidine make in the name of the reaction product with 5-s ' yield after flash chromatography and repeated recrystallization from a mixture of methylene chloride/ether: so pl. 192 194oC.

IR (KBR): 3410, 3180, 2930, 2825, 1715, 1490, 705.

Analysis calculated for C21H24N2O30.5 N2O, 69,79; N. OF 6.96; N 7,75.

Found, 69,77; N. Of 6.52; N 7,60.

Example 11.

6-[2-(4-Hydroxy-4-phenylpiperidine)-1-oxyethyl]-2(3H)-benzoxazolone

According to the methods of examples 8 and 2, 6-(2-chloroacetyl)-2(1H)-benzoxazolone and 4-hydroxy-4-phenylpiperidine make in the name of the reaction product with a 25-s ' yield after recrystallization from a mixture of ethanol/ether: so pl. 175 177oC.

NMR (methanol-D4): 7,51 (two doublet, J 1.5 and 8.5 Hz, 2H), 7,35 - 7,29 (multiplet, 3H), 7.24 to 7,19 (multiplet, 2H), 7,05 (doublet, J 8 Hz, 1H), 4,94 4,90 (mult is, N), 2,19 (doublet and Quartet, J 4.5 and 13 Hz, 2H), 1,74 (broadened doublet, J 14,5 Hz, 2H).

IR (KBR): 3320, 3115, 2920, 2830, 1785, 1750.

Example 12.

6-[2S*-(4-Hydroxy-4-phenylpiperidine)-1S*-oksipropil] -3,4-dihydro-2(1H)-hinolan

According to the methods of examples 1 and 2, 5-(2-chloropropionyl)-3,4-dihydro-2(1H)-hinolan and 4-hydroxy-4-phenylpiperidine make in the name of the reaction product obtained in the form of a white solid with 28 th yield after flash chromatography and recrystallization from ethyl acetate: so pl. 218 219oC.

NMR 7,92 (singlet, 1H): 7,52 (triplet, partially hidden by the NMR signals of the solvent, J 7 Hz, 1H), 7,20 (singlet, 1H), 7,14 (doublet, J 8 Hz, 1H), 6,70 (doublet, J 8 Hz, 1H), 5,27 (broadened singlet, 1H), 4,22 (doublet, J 10 Hz, 1H), 3,09 (triplet, J 11 Hz, 1H), 2,96 (triplet, J 7 Hz, 2H), 2,73 2,58 (multiplet, 6N), 2,32 2,05 (multiplet, 2H), 1,86 (broadened doublet, J 14 Hz, 2H), 1.57 in (singlet, 1H), 0.84 (doublet, J 6.5 Hz, 3H).

Analysis, wickline for C23H28N2O3WITH 72,60; N 7,42; N OF 7.36.

Found, 72,16; N 7,34; N 7,29

Example 13.

5-[2S*-(3-(4-Chlorophenylthio)-8-azabicyclo[3.2.1]-Oct-8-yl)-1S*-oksipropil]-2(1H,3H)-indole

According to the methods of examples 1 and 2 make 3-(4-chlorophenylthio)-8-azabicyclo[3.2.1] -octane presented in Vim 1R*THAT 2R*-isomer: so pl. 146 - 158oC.

Example 14.

6-[2S*-(3-Phenylthio-8-azabicyclo[3.2.2] -Oct-8-yl)-1S*-oksipropil]-3,4-dihydro-2(1H)-hinolan

According to the methods of examples 1 and 2 turn 6-(2-chloropropionyl)-3,4-dihydro-2(1H)-hinolan and 3 phenylthio-8-azabicyclo[3.2.1]-octane in the name of the reaction product with 15-s ' output, so pl. 144 145oC (from ethyl acetate).

Example 15.

5-Chloro-6-[2R*-(4-hydroxy-4-phenylpiperidine)1S*-oksipropil]-2(3H)-benzoxazolone

According to the methods of examples 1 and 2 make 5-chloro-6-(2-chloropropionyl)-2(1H)-benzoxazolone and 4-hydroxy-4-phenylpiperidine in the above in the title of the reaction product with 79% output: so pl. 198 - 199oC (from ethanol).

Example 16.

5-[2S*-(3-Hydroxy-3-phenyl-8-azabicyclo[3.2.1] -Oct-8-yl) -1S*-oksipropil]-2(1H,3H)-indole

According to the methods of examples 1 and 2 make 3-hydroxy-3-phenyl-8-azabicyclo[3.2.1]-octane in the above in the title of the reaction product.

Example 17.

5-[2S*-(3-Benzyl-3-hydroxy-8-azabicyclo [3.2.1] -Oct-8-yl)-1S*-oksipropil] -2(1H,3H)-indole

According to the methods of examples 1 and 2 make 3-benzyl-3-hydroxy-8-azabicyclo[3.2.1]-octane in the above in the name of the product Rea is sapropel] -2(1H,3H)-indolene

Method AND

A mixture of (+)-camphorsulfonic acid (232 mg, 1 mmol) is mixed with the above reaction product of example 3 (366 mg, 1 mmol) in 25 ml of ethanol. Formed almost transparent homogeneous solution before the salt starts to precipitate. After standing at ambient temperature overnight, the salt is collected, washed with ethanol and dried under a stream of nitrogen. Thus obtained 460 mg pink salt is recrystallized four times from ethanol. The obtained reaction product weighs 260 mg and has so pl. 241 - 242,5oAnd []Na+ 19,0o(c 0,295, methanol), showing that it is divided only in part.

Method B.

To a mixture of CH2CL2(25 ml) and DMF (1 ml) is added above in the header of the reaction product of example 3 (0,366 g, 1 mmol), dicyclohexylcarbodiimide (0,266 g, 1.1 mmol), 1-hydroxy-benzotriazole (0,148 g, 1.1 mmol), 4-dimethylaminopyridine (0,134 g, 1.1 mmol) and N-tert-butyloxycarbonyl-L-alanine (0,189 g, 1 mmol). The mixture is stirred under nitrogen atmosphere overnight. The homogeneous solution was diluted with ethyl acetate (25 ml) and filtered through Celite (TM) to remove dicyclohexylphosphino. The filtrate is concentrated and transferred to the ethyl acetate (150 ml). The second filter removes even iCl and saline. The organic phase is dried over calcium sulfate and concentrated to an oily foamy substance. Flash chromatography on silica gel (50 x 100 mm (2 x 4 inches) filled with 50 ethyl acetate/hexane) by elution with 75 ethyl acetate/hexane first, 0.1 g of almost pure diastereoisomer alanine adduct. Then, 0.2 g of a mixture of diastereomers and, finally, 0.1 g of partially enriched sample of the other diastereoisomer. A sample weighing 0.2 g re chromatographic in the same way to get another 0.06 g of the first pure diastereoisomer. The combined reaction product weighing 0.16 g recrystallized from ethyl acetate/hexane, to obtain 0,094 g of the adduct in the form of a white solid substance; so pl. 189 190oC.

NMR (DCl3): to 7.61 (broadened singlet, 1H D2O blurs the signal) of 7.48 (two doublet, J 1.5 and 8 Hz, 2H), 7,37 (triplet, J 7.5 Hz, 2H), 7,34 7,18 (multiplet, 3H), 6,83 (doublet, J 8 Hz, 1H), 5,76 (doublet, J 10 Hz, 1H), 5,19 (broadened doublet, J 7 Hz, 1H), 4,37 (broadened triplet, J 7 Hz, 1H), 3,54 (singlet, 2H), 3,06 2,90 (multiplet, 2H), 2,84 2,52 (multiplet, 3H), 2,16 of 1.88 (multiplet, 2H), 1,82 1,69 (multiplet, 2H), 1,52 (doublet, J 7 Hz, 3H), 1,40 (singlet, N), 0,78 (doublet, J 7 Hz, 3H), []D+ 69,5o(0.295 in methanol).

Analysis calculated DL is butiloxinazola-alanine adduct (0,047 g, 0,087 mmol) dissolved in 9 ml of 0.32 N solution of sodium methoxide (0.15 g Na was dissolved in 20 ml of methanol). The mixture is stirred for 2 h and the solvent is removed at ambient temperature under vacuum. The residue is dissolved in ethyl acetate and extracted with aqueous bicarbonate and brine. The organic phase is dried over calcium sulfate and concentrated. The crude reaction product is subjected to flash chromatography on silica gel (1 x 2 inch 25 x 50 mm). After washing the column with 50 ethyl acetate/hexane, completely separated programalso the reaction product elute with ethyl acetate: 0,011 g (34).

[]D+ 45,3o(c 0,19 in methanol).

The opposite enantiomer get a similar manner from N-tert-butyloxycarbonyl-D-alanine, but in the reaction combinations using carbonyl-diimidazole. Carbonyl-diimidazole (0,42 g, 2 mmol) are added at once at once to a stirred solution of N-tert-butyloxycarbonyl-D-alanine (from 0.76 g, 2 mmol)in methylene chloride (80 ml). The mixture is stirred for 1 h, then add all named under the reaction product from example 3 (0,366 g, 1 mmol) and the reaction mixture was stirred over night. The mixture is diluted with methylene chloride and extraparochial (2 x 7 inches, 50 x 175 mm). Elution with 25 ethyl acetate/hexane followed by 50 ethyl acetate/hexane, gives of 0.13 g of the target diastereoisomer, recrystallized from ethyl acetate/hexane, to obtain 0,077 g purified substances; so pl. 187 188oC. []D- 64,1o(0,17 in methanol). This substance hydrolyzing a methanol solution of sodium methoxide, in the above method, to obtain presents in the header of the reaction product with 85-s ' output: []D- 40,5o(c 0.21 in methanol). Subsequent elution with the above flash chromatography gives the other diastereoisomer, polluted the first reaction product.

Example 19.

7-Fluoro-5-[2-(4-hydroxy-4-phenylpiperidine)-propionyl]-2-(1H,3H)-indole

A mixture of 7-fluoro-5-(2-chloropropionyl)-2(1H,3H)-indolene (1.0 g, 4.14 mmol), 4-hydroxy-4-phenylpiperidine (0.74 g, to 4.17 mmol) and triethylamine (1.2 ml, 8.6 mmol) in anhydrous dimethylformamide is heated to 70 to 90oC for 3 hours the Mixture is poured into 1 N aqueous LiCl and extracted with two portions of ethyl acetate. The combined organic phase is washed with 1N Hcl, water and brine. The organic phase is dried over magnesium sulfate, filtered and concentrated to 1.6 g of a reddish solid. The crude reaction product of acidity of 0.58 g of the desired product of the reaction. This reaction product is optionally purified by recrystallization from a mixture of acetonitrile/ether to obtain 0.2 g of a light yellow substance: so pl. 197 199,5o. NMR (DMSO d6): 11,25 (singlet, 1H), of 7.90 (doublet, J and 11.6 Hz, 1H), 7,82 (singlet, 1H), 7,42 (doublet, J 7.2 Hz, 2H), 7,28 (triplet, J 7.4 Hz, 2H), 7,17 (triplet, J 7.2 Hz, 1H), 4,76 (singlet, 1H), 4,25 (Quartet, J 6.6 Hz, 1H), 3,66 (singlet, 2H), 2,88 2,63 (multiplet, 2H), 2,60 2,55 (multiplet, 1H), 2,49 of 2.38 (multiplet, 1H), 1,88 (doublet and triplet, J 12.2 and a 4.3 Hz, 1H), 1.77 in 1,49 (multiplet, 3H), 1,16 (doublet, J 6.6 Hz, 3H),

The Queen re-chromatographic to get another 0.15 g of the reaction product with a total yield 0.35 g (22).

Analysis calculated for C22H23FN2O3WITH 69,09; N THE 6.06; N 7,32.

Found, 68,36; N. Of 5.85; N 7,31.

Example 20.

7-Fluoro-5-[2S*-(4-hydroxy-4-phenylpiperidine)-1S*-(4-hydroxy-4-phenylpiperidine)-1S*-oksipropil]-2(1H,3H)-indole

Borohydride sodium (0,033 g, 0,872 mmol dissolved in absolute ethanol (3 ml) and the whole ketone the reaction product of the above reaction (3.0 g, 0.78 mmol) is added at once in the form of solids. The reaction mixture was further diluted with 10 ml of ethanol. The mixture is stirred in a stream of nitrogen for 2 hours, the Excess hydride is quenched with water and the mixture is th is washed with saline, dried over magnesium sulfate and concentrated to a glassy solid. This substance is subjected to flash chromatography on silica gel (1 x 4 inches 25 x 100 mm). Elution with 50 ethyl acetate/hexane, then 100-aqueous ethyl acetate to give 0.2 g of a white solid. Further purification by recrystallization from acetonitrile/ethyl acetate to give 0.1 g (33) of the reaction product in the form of a white powder: so pl. 225 227oC.

NMR (DMSO d6: 10,83 (broadened singlet, 1H), 7,54 (doublet, J and 7.3 Hz, 2H), 7,33 (triplet, J a 7.6 Hz, 2H), 7,21 (triplet, J 7,3 Hz, 1H), 7,07 (triplet, J 5.3 Hz, 2H), 5,09 (broadened singlet, 1H), 4,82 (singlet, 1H), 4.26 deaths (doublet, J 9.3 Hz, 1H), 3,56 (singlet, 2H), 2,97 (triplet, J is 10.6 Hz, 1H), 2,62 2,56 (multiplet, 4H), 1,92 2,12 (multiplet, 2H), 1,63 (broadened doublet, J 12.9 Hz, 2H), 0.74 and (doublet, J 6.6 Hz, 3H).

Analysis calculated for C22H25FN2O3C 68,73; N 6,55; N 7,29.

Found, 68,53; N. Of 6.31; N 7,13.

Examples 21 to 30.

According to the methods of the previous examples have the following additional connections (see the output in the final stage, the melting temperature and the solvent from which to allocate the connection).

21. 6-[1S*-Hydroxy-2S*-(4-hydroxy-4-(4-were) -piperidino)-propyl]-3,4-dihydr peridine)-propyl] -2(1H, 3H)-indole: 1,7 so pl. 200 203oC (ether).

23. 5-[1S*-Hydroxy-2S*-(3-phenylthio-8-azabicyclo[3.2.1]-Oct-8-yl)-propyl] -2(1H,3H)-indole: 12 so pl. 159 - 160oWith (ethyl acetate/acetonitrile).

24. 5-[1R*-Hydroxy-2S*-(3-phenylthio-8-azabicyclo[3.2.1]-Oct-8-yl)-propyl] -2(1H,3H)-indole: 7 so pl. 211 - 212oWith (ethyl acetate/acetonitrile).

25. 7-Fluoro-5-[1S*-hydroxy-2S*-(4-hydroxy-4-phenylpiperidine)-propyl] -2(1H, 3H)-indole: 33 so pl. 225 227oWith (ethyl acetate/acetonitrile).

26. 4-Chloro-5-[1S*-hydroxy-2S*-(4-hydroxy-4-phenylpiperidine)-propyl] -2(1H, 3H)-indole: 31 so pl. 231 233oC (ethanol/ether).

27. 4-Chloro-5-[1R*-hydroxy-2S*-(4-hydroxy-4-phenylpiperidine)-propyl] -2(1H, 3H)-indole: 14 so pl. 213,5 218oC (ethanol/ether).

28. 5-[1S*-Hydroxy-2S*-(4-hydroxy-4-phenylpiperidine) -propyl] -7-methyl-2(1H, 3H)-indole: 14 so pl. 227,5 230oC (ethanol/dimethyl sulfoxide).

29. 5-[1S*-hydroxy-2S*-(4-hydroxy-4-phenylpiperidine) -propyl] -4-methyl-2(1H, 3H)-indole: 22 so pl. 241 242oC (ethanol/dimethyl sulfoxide).

Preparation 1.

5-Cyano-1(pair-toluensulfonyl)-indole

Sodium hydride (8,4 g, 210 mmol) was washed twice with hexane, and then suspended in tetrahydrofuran (500 ml). 5-Cyano-ind environment for 1 h, and then add a pair of toluensulfonyl chloride (26.7 g, 140 mmol) in tetrahydrofuran (200 ml). The reaction mixture is stirred for further 3 h, followed by addition of water. The phases are separated and the aqueous phase is extracted twice with ethyl acetate. The combined organic phase was washed with brine, dried over calcium sulfate and concentrated. The residue is recrystallized from ether to obtain 29,97 g, 72 named in the header of the reaction product: so pl. 129 131oC.

NMR 9,04 (doublet, J 8.5 Hz, 1H), 7,85 (doublet, J 1 Hz, 1H), 7,75 (doublet, J 9 Hz, 2H), to 7.67 (doublet, J 3.5 Hz, 1H), 7,53 (multiplet, 1H), 7.23 percent (multiplet, 2H), 6,68 (doublet, J 3.5 Hz, 1H), 2,34 (singlet, 3H).

IR (l3the solution): 2225, 1597, 1453, 1380, 1289, 1266, 1169, 1138, 1123, 1089 (shoulder), 990.

FAB HRMS calculated for C16H13N2O2S (MH+): 297,0669.

The observed m/e: 297,0685.

The drug 2.

5-Propionyl 1-(para-toluensulfonyl)-indole

The reaction product from the previous preparation (11.4 g, 40 mmol) dissolved in dry toluene (760 ml) and cooled to 0oC. are added dropwise, etimani bromide (14 ml, 42 mmol, 3M) in 40 ml of dry toluene. The mixture is heated to 58oC for 24 h, cooled and quenched with water (60 ml) and 1N Hcl (60 ml) per the definition phase is washed with saline, dried over calcium sulfate and concentrated. The residue is recrystallized from ethyl acetate to obtain 6.8 g, 64 provided in the header of the reaction product in the form of a yellow solid: so pl. 162 164oC.

NMR 8,16 (doublet, J 1.5 Hz, 1H), 8,01 (doublet, J 8.5 Hz, 1H), 7,94 (two doublet, J 1.5 and 8.5 Hz, 1H), 7,75 (doublet, J 8.5 Hz, 2H), 7.62mm (doublet, J 3.5 Hz, 1H), 7.23 percent (doublet, J 8.5 Hz, 2H), 6,72 (doublet, J 3.5 Hz, 1H), 3,02 (Quartet, J 7 Hz, 2H), 2,33 (singlet, 3H), 1,21 (triplet, J 7 Hz, 3H).

The drug 3.

5-(2-Bromopropionyl)-1-(para-toluensulfonyl)-indole

The reaction product from the previous preparation (2.0 g, 6.12 mmol) dissolved in chloroform (60 ml) and added dropwise to a suspension of copper bromide (2) (2.1 g, 9.4 mmol) in ethyl acetate (60 ml). The resulting mixture was refluxed over night. The reaction mixture was cooled and filtered through a layer of celite and concentrate. The residue is recrystallized from ethyl acetate/hexane, to obtain 1.70 g, 69 presented in the title of the reaction product as a brown solid. NMR analysis of this substance shows that it is 83/17 mixture of reaction product and educt, which is used in the reaction combinations without additional purification.

NMR sign (multiplet, 2H), 6.73 x (doublet, J 4 Hz, 1H), 5,31 (Quartet, J 6.5 Hz, 1H), 2,32 (singlet, 3H), 1,87 (doublet, J 6.5 Hz, 3H).

The drug 4.

0-Methansulfonate

According to the (14.2 g, 100 mmol) dissolved in CH2Cl2(210 ml) and triethylamine (23 ml, 160 mmol) is added to the solution. Methanesulfonyl chloride (9.3 ml, 120 mmol) is added rapidly dropwise, causing a quiet boiling reverse drains phlegmy solution with methylene chloride. The mixture is stirred for another hour, then extracted with cold of 0.5 molar sodium hydroxide, water and brine, dried by filtration through phase separating paper and concentrate to obtain 13.8 g (65) named in the header of the reaction product as a yellow solid.

NMR 4,88 (triplet, J 5 Hz, 1H), 3,10 3,05 (multiplet, 2H), 2,94 (singlet, 3H), 2,22 (singlet, 3H), 2,20 2,10 (multiplet, 2H), 2,02 1,88 (multiplet, 6N).

The drug 5.

3 Phenylthio-8-methyl-8-azabicyclo[3.2.1]-octane

NaH (60 in oil: 2,77 g, 60 mmol) was washed with hexane (three times), and then suspended in tetrahydrofuran (300 ml). Thiophenol (6.5 ml, 63 mmol) in tetrahydrofuran (25 ml) is added dropwise within 5 minutes Molokoobraznuyu a white slurry, which is formed with evolution of hydrogen, and stirred at the boil camping with reverse drains phlegmy during the night, cooled and filtered through diatomaceous earth with washing with ether. The filtrate is diluted with ethyl acetate and washed with cold 1M NaOH, water and brine, dried (SO4) and concentrate to obtain 11,48 g (78) named in the title of the reaction product as a yellow solid.

NMR 7,50 7,18 (multiplet, 5H), 3,32 3,21 (multiplet, 1H), 3,15 - 3,09 (multiplet, 2H), 2,25 (singlet, 3H), 1,94 2,02 (multiplet, 2H), 1,72 1,79 (multiplet, 4H), 1,60 1,51 (multiplet, 2H).

13C-NMR: 134,8, 132,3, 128,8, 126,9, 61,16, 39,21, 38,38, 37,72, 26,42.

In the same way turn 4-chlorothiophenol 3-(4-chlorophenylthio)-8-methyl-8-azabicyclo[3.2.1]-octane.

The drug 6.

3 Phenylthio-8-(2,2,2-trichlorocyanuric)-8-azabicyclo[3.2.1]-octane

Named in the header of the reaction product from the previous preparation (11,48 g, to 49.3 mmol) and K2CO3(0.75 g, 5.4 mmol) is mixed with benzene (200 ml) and quickly add 2,2,2-trichlorethylene ether of Harborview acid (7.5 ml, of 54.4 mmol). The reaction mixture is boiled with reverse drains phlegmy for 2 h, cooled, filtered and concentrated. The orange oily residue was dissolved in CH2Cl2and washed with a saturated solution of NaHCO3and then brine, visum 5 ethyl acetate/hexane used as the eluate), to get a first unreacted thiophenol from the previous reaction, and then called in the header of the reaction product as a yellow oil (13 g, 67).

NMR 7,42 of 7.23 (multiplet, 5H), 4.72 in (AB Quartet, J 12 Hz, 2H), 4,35 4,30 (multiplet, 4H), 2,73 (septet, J 6 Hz, 1H), 2.05 is 1,68 (multiplet, 6N).

The oil hardens by grinding into powder with hexane; so pl. 83 84,5oC.

Analysis:

Calculated With 48,47; N 4,58; N 3,49.

Calculated With 48,68; N 4,69; N 3,55.

In the same way turn 4-chloro-similar to the previous product 3-(4-chlorophenylthio)-8-(2,2,2-trichlorocyanuric)-8-azabicyclo[3.2.1]-octane.

The drug 7.

Named in the title of the reaction product from the previous preparation (13,0 g, 33 mmol) is dissolved in acetic acid (400 ml) and added zinc powder (11 g, 168 mmol). The mixture is heated to 100oWith overnight, then concentrated and the residue separated into pieces between layers of CH2Cl2and a saturated solution of NaHCO3. The resulting emulsion lighten filtered through diatomaceous earth. The phases are separated and the organic layer is dried using futuredeluxe filter paper and concentrated to obtain 6,1 g (84) named in the title of the product Rea (singlet; 2H), 3,36 (septet, J 6 Hz, 1H), 1,94 - 1,54 (multiplet, 8H),13C-NMR 134,0, 132,43, 128,83, 127,06, 54,93, 40,81, 39,01, 28,98.

In the same way turn 4-chloro-similar to the previous product 3-(4-chlorophenylthio)-8-azabicyclo[3.2.1]-octane.

The drug 8.

8-(2,2,2-Trichlorocyanuric)-3-endo-hydroxy-3-Exo-phenyl-8-azabicyclo[3.2.1]-octane

8-(2,2,2-Trichlorocyanuric)-3-endo-hydroxy-3-Exo-phenyl-8-azabicyclo[3.2.1] -Octan-3-one (5.0 g, of 16.6 mmol) dissolved in ether (450 ml) and added dropwise over 5 min with stirring fenermine bromide (7.2 ml, 21.6 mmol, 3M in ether). A white precipitate is formed and the mixture is stirred for 30 minutes Add a saturated solution of ammonium chloride and the mixture concentrated. The residue is dissolved in methylene chloride and extracted with salt solution. The organic phase is optionally dried using a phase-separating filter paper and concentrated to get named in the header of the reaction product as a thick yellow oil (5,94 g, 94). This substance is used in the next reaction without further purification.

Homologous 3-Exo-benzyl derivative gain in a similar way, replacing fenermine bromide on benslimane bromide.

The drug 9.

2PO4) (45 ml). The mixture is stirred for 3 days. Then add water (100 ml) and the pH was adjusted to about 10 by addition of solid sodium carbonate. The mixture is filtered through Celite (TM) and concentrate to obtain 1.85 g (58) provided in the header of the reaction product in the form of a white solid. Integration of the NMR spectrum for bridging protons of the reaction product shows that it consists of a 92: 8 mixture of the desired product of the reaction ( 3.6) and its 3-endogenising isomer (d 3,85). This mixture is used as such for the reaction mixture, as the separation of the reaction products of the combination is easy.

13C-NMR (300 MHz, DCl3) Delta: 150,42, 128,15, 126,57, 124,52, 73,33, 54,45, 46,62, 29,29.

Minor isomer shows aliphatic13C signals at d 54,92, 50,99, 30,33, 30,16.

Homologous 3-Exo-benzyl derivative gain this way.

Tests neurodegeneration cell culture

Cell culture. Hippocampal cells 17 day fetal rats (SD, CALs river) were cultured on culture plates mayoralty (firm Falcon, Lincoln, PCs, new Jersey, USA) for 2 to 3 weeks in serum, containing glutamine, 21 mmol glucose, penicillin/streptomycin (5000 units each), 10 fetal bovine (1 to 7 day) and horse serum (1 to 21 days). Cells were seeded on plates with 96 wells microtitre with a density of 80 thousand cells in 1 hole, or on plates with 24 wells cultures with a density of 250 thousand in 1 hole. The cultures were grown at 37oWith moist tissue culture incubator containing 5 CO2and 95 air. Reproduction of non-neuronal cells was controlled by the addition of 20 µm uridine and 20 Microm 5-fluoro-2-deoxyuridine (company Sigma chemical Co. St. Louis, PCs Missouri) at 6 - 8 days of cultivation. The culture medium was replaced every 2 to 3 days at the latest.

Glutamate toxicity. Culture was estimated on glutamate toxicity in 2 to 3 weeks from the start of cultivation. Remove culture medium and the culture was twice washed controlled saline; sodium chloride (120 mmol), potassium chloride (5.4 mmol), magnesium chloride (0.8 mmol/l), calcium chloride (1.8 mmol), glucose (15 mmol); and buffer EPES (25 mmol/l, pH 7.4). Then the cultures were subjected to different concentrations of glutamate at 37oC, 15 minutes After this incubation, the cultures were washed 3 times in a controlled salt solution without potamoi medium without serum. Drugs were added 2 min prior to and during the 15 min exposure to glutamate. In some experiments, drugs were added at various times after exposure to glutamate and over the next 20 24 PM

Cell survival was determined in a standard way through 20 24 h after exposure excitation, by measuring the activity zitozolnah enzyme lactate-dehydrogenase (LDH). The activity of LDH was determined to culture medium to each of the 96 wells micromicrofarad plates. The sample (50 μl) of medium was added to equal volume of sodium phosphate buffer (0.1 mmol/l, pH 7.4) containing 1,32 mmol/l sodium pyruvate and 2.9 mmol/l ADN. For each of the 96 wells was measured by UV-absorption of the entire reaction mixture at 340 nm every 5 seconds, for 2 min using an automated spectrophotometric analyzer mikitarian plates (company Molecular devices, Menlo Park, PCs California). The degree of absorption was calculated automatically using IBM Softmax (version 1,01, the company Molecular devices), and it was used as an index, the activity of LDH.

Morphological assessment of neuronal survival was determined using phase contrast is a group of therefore, for this purpose, we used cells cultured on 24-hole plates. Quantitatively both cultural sowing were equally sensitive to glutamate toxicity and showed a 2-3-fold increase in LDH activity 24 hours after exposure to 0.1 to 1.0 mmol/l glutamate.

The reagents. Prazosin was synthesized firm Pfizer, 1,3-di-ortho-tolylguanidine was set by the company Aldrich (Milwaukee, pieces of Viscose), MC-901, AG-7, 3-PPP (3-(3-hydroxyphenyl)-N-propylpiperidine, and Heloderma were delivered by firm research Biochemicals Inc. (NATICK, pieces Massachusetts). Spermin was supplied by Sigma (St. Louis, Missouri). Horse and fetal bovine serum were supplied by Hanlon (Logan, PCs Uta). Cultural medium, glutamine, and penicillin/streptomycin were supplied by the company the Flexibility To. (Grand island, PCs, new York.

Analysis of the data. Neurotoxicity was characterized quantitatively by measurement of LDH activity present in the culture medium 20 24 h after exposure to glutamate. Our initial experiments confirmed the published message indicating that the increased activity of LDH in the culture medium correlates with the destruction and degeneration of neurons. As is the R buffer nursing holes of the same cultural planting. In order to get the index of the activity of LDH for cultures treated with glutamate and medication, LDH values for the control cultures were subtracted from the values for LDH-treated groups. Data for medical treatments were expressed as the percentage increase of LDH induced by 1 mmol/l glutamate (or N) for each experiment. The concentration of N-antagonists, which are required to return 50 increase in LDH induced exitotoxins (IC50), were calculated using logarithmico-probabilistic analysis of the summary results of three independent experiments. Different groups of treatment were compared using dvukhkontsevoi criterion t.

1. Derivatives indolene General formula

< / BR>
where X denotes

< / BR>
< / BR>
or

< / BR>
where a is a group of formula B

< / BR>
< / BR>
n is 0 or 1;

m is 0 or an integer from 1 to 6;

R, R1and R2each independently is hydrogen or C1C3by alkyl;

R3and R4taken separately, each is hydrogen or taken together are ethylene;

X1is hydrogen, C1C3alkoxygroup or C1C3-alkoxy-carbon is-alkyl, C1C3-alkoxygroup, fluorine, chlorine or bromine,

in the form of a racemate or an optically active isomer or pharmaceutically acceptable salt additive acid.

2. Connection on p. 1, wherein m is 0 or 1, Z and Z'each is hydrogen, and R2methyl or hydrogen.

3. Connection on p. 2, wherein R2is stands and has a relative stereochemical formula

< / BR>
4. Connection on p. 3, wherein R3and R4taken separately, each represents hydrogen.

5. Connection on p. 4, wherein M is 0.

6. Connection on p. 3, wherein R3and R4together form ethylene.

7. The compound of formula II under item 1, wherein Z is hydrogen and Z'is hydrogen or chlorine, R2methyl.

8. Connection on p. 7, characterized in that it has a relative stereochemical formula

< / BR>
where R and R1each is hydrogen, and Y is CH2.

9. Connection on p. 1, wherein Z and Z'each is hydrogen or stands, m is 0 or 1.

10. Ketoprofene indolene General formula


n is 0 or 1;

m is 0 or an integer from 1 to 6;

R, R1and R2each independently is hydrogen or C1C3-alkyl;

R3and R4are treated separately and each is hydrogen or R3and R4considered together are ethylene;

X1is hydrogen, C1C3-alkoxygroup or C1C3-alkoxycarbonyl;

Y is CH2or oxygen;

Z and Z'each independently is hydrogen, C1- C3-alkyl, C1C3-alkoxygroup, fluorine, chlorine or bromine.

 

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BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

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BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

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The invention relates to new biologically active chemical compounds, namely, to derive a cyclic amide of the formula I

R1-(CH2)n-Z,

where R1group cyclic amide, such as 2H-3,4-dihydro-1,3-benzoxazin-2-she, 2H-3,4-dihydro-1,3-benzoxazin-2,4-dione, and 1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1,2,3,4-tetrahydroquinazolin-2-it, 1,2,3,4-tetrahydropyrido(3,2-d)-pyrimidine-2,4 - dione, and 1,2,3,4-tetrahydropyrido(3,2-d)pyrimidine-2-it, 1,2,3,4-tetrahydropyrimidine-2,4-dione, pyrrolidin-2-it, 1,2,3,4 - tetrahydropyridine-2-it, 5H-6,7,8,9-tetrahydropyrido(3,2-b)azepin-6-she N-5,6,7,8-tetrahydropyrido(2,3-b)azepin - 8-she, 2H-3,4-dihydropyrido(2,3-e)-1, 3-oxazin-2-thione or 2-she pyrrolidine (3,4-b)-pyrazin-5-she 1H-2,3,4,5-tetrahydrothieno(2,3-b)indol-2-it, 8H-4,5,6,7-tetrahydrothieno(2,3-b)thiophene-7-she 4H-pyrazolo(5,4-f)benzazepin-9-it, isoindoline-1,3-dione, benzoxazolyl-2-it, unsubstituted or substituted lower alkyl, lower alkoxy, halogen, the nitro-group, carboxy, benzoyl or benzyl, n is zero or an integer from 1 to 6, Z is a group of formula (A) or (B):

N-(CH2)mR2(A) or -(CH2)p, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene, m is an integer from 1 to 3; R3is lower alkyl; R4is phenyl or a radical of dioxolane, furan or thiophene, p = 1, provided that when R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R4are not phenyl or substituted by a halogen phenyl, or their pharmacologically acceptable salts with antiacetylcholinesterase activity

The invention relates to medicine, namely to anesthesiology, and can be used in anesthetic ensuring operations on the brain

The invention relates to medicine, and concerns the use of CIS-1-(33-acetylthiophene)-6-methylpiperidine acid, known as compounds having antihypertensive activity, as a means for the treatment of acute and chronic heart failure
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